Methods of treating a neurological or psychiatric disorder

ABSTRACT

Provided are methods of treating a neurological or psychiatric disorder in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof in combination with an amount of one or more compounds effective to increase the level of nicotinamide adenine dinucleotide (NAD+) in the subject.

Provided herein are methods of treating a neurological or psychiatricdisorder in a subject in need thereof.

Ketamine is a nonbarbiturate general anesthetic chemically designated dl2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

Esketamine is the S-isomer, i.e., (S)-ketamine or S(+)-ketamine. Inaddition to its anesthetic effects, esketamine shows properties of beinga rapid-acting antidepressant.

Arketamine, also (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−)enantiomer of ketamine. Arketamine is biologically active; however, itis less potent as an NMDA receptor antagonist and anesthetic and thushas not been approved or marketed for clinical use as an enantiopuredrug.

NADH stands for “nicotinamide adenine dinucleotide (NAD)+hydrogen (H).”This chemical occurs naturally in the body and plays a role in thechemical process that generates energy.

There is a significant, unmet need for methods for treating aneurological or psychiatric disorder. The present disclosure fulfillsthese and other needs, as evident in reference to the followingdisclosure.

Provided are methods of treating a neurological or psychiatric disorderin a subject in need thereof, comprising: administering to the subject atherapeutically effective amount of ketamine or a pharmaceuticallyacceptable salt thereof in combination with an amount of one or morecompounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) in the subject.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds, and/or compositions, and are eachhereby incorporated by reference in their entirety.

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” or “some embodiments” or “a certain embodiment” means that aparticular feature, structure or characteristic described in connectionwith the embodiment is included in at least one embodiment. Thus, theappearances of the phrases “in one embodiment” or “in an embodiment” or“in some embodiments” or “in a certain embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Also, as used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise.

As used herein, “co-administer” and “co-administration” and variantsthereof mean the administration of at least two drugs to a patienteither subsequently, simultaneously, or consequently proximate in timeto one another (e.g., within the same day, or week or period of 30 days,or sufficiently proximate that each of the at least two drugs can besimultaneously detected in the blood plasma). When co-administered, twoor more active agents can be co-formulated as part of the samecomposition or administered as separate formulations. This also may bereferred to herein as “concomitant” administration or variants thereof.

As used herein, “adjusting administration”, “altering administration”,“adjusting dosing”, or “altering dosing” are all equivalent and meantapering off, reducing or increasing the dose of the substance, ceasingto administer the substance to the patient, or substituting a differentactive agent for the substance.

As used herein, “administering to a patient” refers to the process ofintroducing a composition or dosage form into the patient via anart-recognized means of introduction.

As used herein the term “disorder” is intended to be generallysynonymous, and is used interchangeably with, the terms “disease,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms.

As used herein, a “dose” means the measured quantity of an active agentto be taken at one time by a patient.

As used herein, “dosing regimen” means the dose of an active agent takenat a first time by a patient and the interval (time or symptomatic) atwhich any subsequent doses of the active agent are taken by the patient.The additional doses of the active agent can be different from the dosetaken at the first time.

As used herein, “effective amount” and “therapeutically effectiveamount” of an agent, compound, drug, composition or combination is anamount which is nontoxic and effective for producing some desiredtherapeutic effect upon administration to a subject or patient (e.g., ahuman subject or patient). The precise therapeutically effective amountfor a subject may depend upon, e.g., the subject's size and health, thenature and extent of the condition, the therapeutics or combination oftherapeutics selected for administration, and other variables known tothose of skill in the art. The effective amount for a given situation isdetermined by routine experimentation and is within the judgment of theclinician.

As used herein, “patient” or “individual” or “subject” means a mammal,including a human, for whom or which therapy is desired, and generallyrefers to the recipient of the therapy.

As used herein, “pharmaceutically acceptable” refers to a material thatis not biologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration.

“Pharmacologically active” (or simply “active”) as in a“pharmacologically active” (or “active”) derivative or analog, refers toa derivative or analog having the same type of pharmacological activityas the parent compound and approximately equivalent in degree.

The term “pharmaceutically acceptable salts” include acid addition saltswhich are formed with inorganic acids such as, for example, hydrochloricor phosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

As used herein, a “product” or “pharmaceutical product” means a dosageform of an active agent plus published material, and optionallypackaging.

As used herein, “treating” or “treatment” refers to therapeuticapplications to slow or stop progression of a disorder, prophylacticapplication to prevent development of a disorder, and/or reversal of adisorder. Reversal of a disorder differs from a therapeutic applicationwhich slows or stops a disorder in that with a method of reversing, notonly is progression of a disorder completely stopped, cellular behavioris moved to some degree, toward a normal state that would be observed inthe absence of the disorder.

As used herein, the term “NAD precursor” refers to molecules that can beconverted/synthesized in vivo into NAD. NAD precursors are known in theart and include, for example, NR and derivatives and analogs thereof(e.g., nicotinoyl ribosides), as well as molecules that can beconverted/synthesized in vivo into NR. For example, certain NADprecursors are discussed in, e.g., WO 2006/116322, WO 2015014722, WO2015186114, WO 2015186068, WO 2016014927, WO 2016/149277, WO 2016049236,WO 2015066382, U.S. Pat. No. 9,408,834, and Kulikova et al., Journal ofBiological Chemistry (2015), 290(45), 27124-27137, each of which isincorporated by reference herein.

Provided is a method of treating a neurological or psychiatric disorderin a subject in need thereof, comprising: administering to the subject atherapeutically effective amount of ketamine or a pharmaceuticallyacceptable salt thereof in combination with an amount of one or morecompounds effective to increase the level of nicotinamide adeninedinucleotide (NAD⁺) in the subject.

In some embodiments, the method for comprises monitoring the subject forneurological deficits. In some embodiments, monitoring determinescognitive functioning and/or pathology.

In some embodiments, the neurological or psychiatric disorder is chosenfrom chronic traumatic encephalopathy, dementia, and neurodegenerativedisease. In some embodiments, the neurological or psychiatric disorderis chronic traumatic encephalopathy. In some embodiments, theneurological or psychiatric disorder is dementia.

In some embodiments, the neurodegenerative disease is chosen fromamyotrophic lateral sclerosis, Alzheimer's Disease, Parkinson's Disease,and Huntington's Disease. In some embodiments, the neurodegenerativedisease is amyotrophic lateral sclerosis. In some embodiments, theneurodegenerative disease is Alzheimer's Disease.

In some embodiments, the neurodegenerative disease is Alzheimer'sDisease and the administration results in inhibiting progression fromMild Cognitive Impairment (MCI) or pre-MCI to dementia stage ofAlzheimer's Disease in the subject. In some embodiments, theneurodegenerative disease is Alzheimer's Disease and the administrationresults in inhibiting progression to dementia stage of Alzheimer'sDisease (AD) in a subject with Down Syndrome or a subject with familialAD mutation.

In some embodiments, the methods result in an increase and/orstimulation of activation of BDNF (brain derived neurotrophic factor).In some embodiments, the methods result in stimulation of neurogenesis.In some embodiments, the methods result in a promotion ofneuroplasticity. In some embodiments, the methods may decrease the levelof tau, amyloid and/or “misfolded” protein deposits in the brain and/ornervous system of the subject.

In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof is administered as esketamine or a pharmaceutically acceptablesalt thereof. In some embodiments, the ketamine or a pharmaceuticallyacceptable salt thereof is administered as arketamine or apharmaceutically acceptable salt thereof. In some embodiments, theketamine or a pharmaceutically acceptable salt thereof is administeredas a pharmaceutically acceptable salt. In some embodiments, thepharmaceutically acceptable salt is the hydrochloride salt.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD+) in the subject isNAD+.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD⁺) in the subject is oneor more NAD⁺ precursors. In some embodiments, the one or more NAD⁺precursors is chosen from nicotinic acid, nicotinamide, nicotinamidemononucleotide (NMN), nicotinamide riboside (NR), or a salt thereof. Insome embodiments, the one or more NAD+ precursors is one or morenicotinamide mononucleotide derivative as described, e.g., in U.S. Pat.No. 9,919,003.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD⁺) in the subject is oneor more NAD boosters. In some embodiments, the one or more NAD boostersis chosen from tryptophan, niacin, N-formylkynurenine, quinolinic acid,and nicotinamide riboside kinase (NRK).

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD⁺) in the subject is anagent that increases the activity of one or more enzymes involved inNAD⁺ biosynthesis. In some embodiments, the one or more enzymes involvedin NAD⁺ biosynthesis is chosen from nicotinate phosphoribosyltransferase 1 (NPT1), pyrazinamidase/nicotinamidase 1 (PNC1), nicotinicacid mononucleotide adenylyltransferase 1 (NMA1), nicotinic acidmononucleotide adenylyltransferase 2 (NMA2), nicotinamideN-methyltransferase (NNMT), nicotinamide phosphoribosyl transferase(NAMPT or NAMPRT), nicotinate/nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2).

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD⁺) in the subject is oneor more compounds that induce NAD+ levels, independent of thestimulation of NAD+ synthesis or the inhibition of NAD+ usage. In someembodiments, the one or more compounds is chosen from activators of AMPactivated kinase (AMPK). In some embodiments, the activators of AMPactivated kinase is chosen5-aminoimidazole-4-carboxamide-1-b-D-riboside, PT-1, A-769662 (Abbott),Adiponectin, Leptin, Ghrelin, Cannabinoids, alpha-lipoic acid,Interleukin-6 (IL-6), Resveratrol, Quercetin, Metformin, Berberine,Curcumine, Epigallocatechin-3-gallate (green tea), Thiazolidinediones,and Dinitrophenol (DNP).

In some embodiments, the subject is also administered vitamins,minerals, and/or supplements.

In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof, is administered as a pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof, with one orpharmaceutically acceptable carriers or excipients.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD⁺) is administered as apharmaceutical composition comprising the one or more compounds, withone or pharmaceutically acceptable carriers or excipients.

The choice of excipient, to a large extent, depends on factors, such asthe particular mode of administration, the effect of the excipient onthe solubility and stability of the active ingredient, and the nature ofthe dosage form.

The pharmaceutical compositions provided herein may be provided in unitdosage forms or multiple-dosage forms. Unit-dosage forms, as usedherein, refer to physically discrete units suitable for administrationto human and animal subjects and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of unit-dosage forms include ampoules and syringes. Unit dosageforms may be administered in fractions or multiples thereof. Amultiple-dosage form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dosage form.

These dosage forms can be prepared according to conventional methods andtechniques known to those skilled in the art. The pharmaceuticalcompositions provided herein may be administered at once, or multipletimes at intervals of time. It is understood that the precise dosage andduration of treatment may vary with the age, weight, and condition ofthe patient being treated, and may be determined empirically using knowntesting protocols or by extrapolation from in vivo or in vitro test ordiagnostic data. It is further understood that for any particularindividual, specific dosage regimens should be adjusted over timeaccording to the individual need and the professional judgment of theperson administering or supervising the administration of theformulations.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science.

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl phydroxybenzates, thimerosal, benzalkonium chloride,benzethonium chloride, methyl- and propylparabens, and sorbic acid.Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin,hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, andsulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In certain embodiments, the pharmaceutical compositions are provided asready-to-use sterile solutions. In certain embodiments, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In certain embodiments, thepharmaceutical compositions are provided as ready-to-use sterilesuspensions. In certain embodiments, the pharmaceutical compositions areprovided as sterile dry insoluble products to be reconstituted with avehicle prior to use. In certain embodiments, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot.

In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof or the one or more compounds is administered intravenously. Insome embodiments, the ketamine or a pharmaceutically acceptable saltthereof or the one or more compounds is administered by infusion. Insome embodiments, the ketamine or a pharmaceutically acceptable saltthereof or the one or more compounds is administered by intravenousbolus, as a continuous intravenous infusion, or a combination thereof.In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof or the one or more compounds is administered as a single bolusinitially, and then administered as a continuous infusion following thebolus. The rate of the infusion can be any rate, e.g., from 1 μg/kg/minto 100 mg/kg/min, or from 1 μg/kg/hr to 1000 mg/kg/hr. Rates of infusioncan include 0.2 to 1.5 mg/kg/min, or more specifically 0.25 to 1mg/kg/min, or even more specifically 0.25 to 0.5 mg/kg/min.

In some embodiments, the infusions are administered once a week over acourse of 2, 3, 4, 5, or 6 weeks. In some embodiments, the infusions areadministered twice a week over a course of 2, 3, 4, 5, or 6 weeks. Insome embodiments, the infusions are administered once or twice a weekover a course of more than 6 weeks. In some embodiments, the infusionsare administered over a course of 2, 3, 4, 5, or 6 weeks and thenmaintenance infusions are subsequently administered every month to everyfew months.

In some embodiments, the methods comprise initially administering theketamine or a pharmaceutically acceptable salt thereof in combinationwith an amount of one or more compounds effective to increase the levelof nicotinamide adenine dinucleotide (NAD+) in the subject byintravenous routes, such as by infusion, and subsequently administeringketamine or a pharmaceutically acceptable salt thereof, optionally incombination, with an amount of one or more compounds effective toincrease the level of nicotinamide adenine dinucleotide (NAD+) in thesubject by a route that is not intravenous. In some embodiments, boththe ketamine or a pharmaceutically acceptable salt thereof and the oneor more compounds are subsequently administered by a non-intravenousroute. In some embodiments, only one of the ketamine or apharmaceutically acceptable salt thereof or the one or more compounds issubsequently administered by a non-intravenous route and the other ofthe ketamine or a pharmaceutically acceptable salt thereof or the one ormore compounds is subsequently administered by an intravenous route.

In some embodiments, the non-intravenous route is oral or topical.

In some embodiments, the non-intravenous route is oral. In someembodiments, the non-intravenous route is buccal, lingual, or sublingualadministration.

In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof is in the form of a tablet, solution, capsule, troche, lozenge,pastille, cachet, pellet, medicated chewing gum, granule, effervescentor non-effervescent powder or granule, emulsion, suspension, wafer,sprinkle, elixir, or syrup.

In some embodiments, the ketamine or a pharmaceutically acceptable saltthereof is administered as a pharmaceutical composition that furthercomprises one or more pharmaceutically acceptable carriers is chosenfrom binders, fillers, diluents, disintegrants, wetting agents,lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, and flavoring agents.

In some embodiments, the pharmaceutical composition comprising ketamineor a pharmaceutically acceptable salt thereof is formulated as amodified release dosage form.

In some embodiments, the pharmaceutical composition comprising ketamineor a pharmaceutically acceptable salt thereof is formulated as adelayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,accelerated- and fast-, targeted-, programmed-release, or gastricretention dosage form.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD+) is in the form of atablet, solution, capsule, troche, lozenge, pastille, cachet, pellet,medicated chewing gum, granule, effervescent or non-effervescent powderor granule, emulsion, suspension, wafer, sprinkle, elixir, or syrup.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD+) is administered as apharmaceutical composition that further comprises one or morepharmaceutically acceptable carriers is chosen from binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

In some embodiments, the pharmaceutical composition comprising one ormore compounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) is formulated as a modified release dosage form.

In some embodiments, the pharmaceutical composition comprising one ormore compounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) is formulated as a delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, or gastric retention dosage form.

In some embodiments, the non-intravenous route of administration istopical administration. In some embodiments, topical administrationcomprises (intra)dermal, conjuctival, intracorneal, intraocular,ophthalmic, auricular, transdermal, nasal, vaginal, uretheral,respiratory, or rectal administration.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof is formulated asan emulsion, solution, suspension, cream, gel, hydrogel, ointment,dusting powder, dressing, elixir, lotion, suspension, tincture, paste,foam, film, aerosol, irrigation, spray, suppository, bandage, or dermalpatch.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof is formulated asliposomes, micelles, microspheres, nanosystems, and mixtures thereof.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof further comprisesone or more pharmaceutically acceptable carriers is chosen from aqueousvehicles, water miscible vehicles, non-aqueous vehicles, antimicrobialagents or preservatives against the growth of microorganisms,stabilizers, solubility enhancers, isotonic agents, buffering agents,antioxidants, local anesthetics, suspending and dispersing agents,wetting or emulsifying agents, complexing agents, sequestering orchelating agents, penetration enhancers, cryopretectants,lyoprotectants, thickening agents, and inert gases.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof is administeredtopically by electroporation, iontophoresis, phonophoresis, sonophoresisand microneedle or needle-free injection.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof thepharmaceutical composition is administered rectally, urethrally,vaginally, or perivaginally in the forms of suppositories, pessaries,bougies, poultices or cataplasm, pastes, powders, dressings, creams,plasters, contraceptives, ointments, solutions, emulsions, suspensions,tampons, gels, foams, sprays, or enemas.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof is administeredintranasally or by inhalation to the respiratory tract.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof is in the form ofan aerosol or solution for delivery using a pressurized container, pump,spray, atomizer, or nebulizer, alone or in combination with a suitablepropellant.

In some embodiments, the pharmaceutical composition comprising theketamine or a pharmaceutically acceptable salt thereof in the form of adry powder for insufflation, alone or in combination with an inertcarrier such as lactose or phospholipids; and nasal drops.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is formulated as an emulsion, solution,suspension, cream, gel, hydrogel, ointment, dusting powder, dressing,elixir, lotion, suspension, tincture, paste, foam, film, aerosol,irrigation, spray, suppository, bandage, or dermal patch.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is formulated as liposomes, micelles,microspheres, nanosystems, and mixtures thereof.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) further comprises one or morepharmaceutically acceptable carriers is chosen from aqueous vehicles,water miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,penetration enhancers, cryopretectants, lyoprotectants, thickeningagents, and inert gases.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free injection.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is administered rectally, urethrally,vaginally, or perivaginally in the forms of suppositories, pessaries,bougies, poultices or cataplasm, pastes, powders, dressings, creams,plasters, contraceptives, ointments, solutions, emulsions, suspensions,tampons, gels, foams, sprays, or enemas.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is administered intranasally or byinhalation to the respiratory tract.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is in the form of an aerosol or solution fordelivery using a pressurized container, pump, spray, atomizer, ornebulizer, alone or in combination with a suitable propellant.

In some embodiments, the pharmaceutical composition comprising the oneor more compounds effective to increase the level of nicotinamideadenine dinucleotide (NAD+) is in the form of a dry powder forinsufflation, alone or in combination with an inert carrier such aslactose or phospholipids; and nasal drops.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

In some embodiments, the ketamine or pharmaceutically acceptable saltthereof will be administered as a subanesthetic dose. In someembodiments, a subanesthetic dose is less than 4.5 mg/kg. In someembodiments, a subanesthetic dose is less than 4 mg/kg. In someembodiments, a subanesthetic dose is less than 3 mg/kg. In someembodiments, a subanesthetic dose is less than 2 mg/kg. In someembodiments, a subanesthetic dose is less than 1 mg/kg. In someembodiments, a subanesthetic dose is less than 0.5 mg/kg.

In some embodiments, the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD+) is administered as asupranormal dose. In some embodiments, a supranormal dose is sufficientto produce a level of NAD+ in excess of those levels normally found asthe result of the body's natural production of NAD+ or that levelinduced by the administration of NAD+ alone.

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. A method of treating a neurological or psychiatric disorder in asubject in need thereof, comprising: administering to the subject atherapeutically effective amount of ketamine or a pharmaceuticallyacceptable salt thereof in combination with an amount of one or morecompounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) in the subject.
 2. The method of claim 1, whereinthe neurological or psychiatric disorder is chosen from chronictraumatic encephalopathy, dementia, and neurodegenerative disease. 3.The method of claim 2, wherein the neurological or psychiatric disorderis chronic traumatic encephalopathy.
 4. The method of claim 2, whereinthe neurological or psychiatric disorder is dementia.
 5. The method ofclaim 2, wherein the neurodegenerative disease is chosen fromamyotrophic lateral sclerosis, Alzheimer's Disease, Parkinson's Disease,and Huntington's Disease.
 6. The method of claim 5, wherein theneurodegenerative disease is amyotrophic lateral sclerosis.
 7. Themethod of claim 5, wherein the neurodegenerative disease is Alzheimer'sDisease.
 8. The method of claim 7, wherein the administration results ininhibiting progression from Mild Cognitive Impairment (MCI) or pre-MCIto dementia stage of Alzheimer's Disease in the subject.
 9. The methodof claim 7, wherein the administration results in inhibiting progressionto dementia stage of Alzheimer's Disease (AD) in a subject with DownSyndrome or a subject with familial AD mutation.
 10. The method of claim1, wherein the ketamine or a pharmaceutically acceptable salt thereof isadministered as esketamine or a pharmaceutically acceptable saltthereof.
 11. The method of claim 1, wherein the ketamine or apharmaceutically acceptable salt thereof is administered as arketamineor a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the ketamine or a pharmaceutically acceptable salt thereof isadministered as a pharmaceutically acceptable salt.
 13. The method ofclaim 12, wherein the pharmaceutically acceptable salt is thehydrochloride salt.
 14. The method of claim 1, wherein the ketamine or apharmaceutically acceptable salt thereof is administered intravenously.15. The method of claim 1, wherein the one or more compounds effectiveto increase the level of nicotinamide adenine dinucleotide (NAD+) in thesubject is NAD+.
 16. The method of claim 1, wherein the one or morecompounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) in the subject is one or more NAD+ precursors. 17.The method of claim 16, wherein the one or more NAD+ precursors ischosen from nicotinic acid, nicotinamide, nicotinamide mononucleotide(NMN), nicotinamide riboside (NR), or a salt thereof.
 18. The method of1, wherein the one or more compounds effective to increase the level ofnicotinamide adenine dinucleotide (NAD+) in the subject is one or moreNAD boosters.
 19. The method of claim 18, wherein the one or more NADboosters is chosen from tryptophan, niacin, N-formylkynurenine,quinolinic acid, and nicotinamide riboside kinase (NRK).
 20. The methodof claim 1, wherein the one or more compounds effective to increase thelevel of nicotinamide adenine dinucleotide (NAD+) in the subject is anagent that increases the activity of one or more enzymes involved inNAD+ biosynthesis.
 21. The method of claim 20, wherein the one or moreenzymes involved in NAD+ biosynthesis is chosen from nicotinatephosphoribosyl transferase 1 (NPT1), pyrazinamidase/nicotinamidase 1(PNC1), nicotinic acid mononucleotide adenylyltransferase 1 (NMA1),nicotinic acid mononucleotide adenylyltransferase 2 (NMA2), nicotinamideN-methyltransferase (NNMT), nicotinamide phosphoribosyl transferase(NAMPT or NAMPRT), nicotinate/nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2).
 22. The method of claim 1, wherein the one ormore compounds effective to increase the level of nicotinamide adeninedinucleotide (NAD+) in the subject is one or more compounds that induceNAD+ levels, independent of the stimulation of NAD+ synthesis or theinhibition of NAD+ usage.
 23. The method of claim 22, wherein the one ormore compounds is chosen from activators of AMP activated kinase (AMPK).24. The method of claim 23, wherein the activators of AMP activatedkinase is chosen 5-aminoimidazole-4-carboxamide-1-b-D-riboside, PT-1,A-769662 (Abbott), Adiponectin, Leptin, Ghrelin, Cannabinoids,alpha-lipoic acid, Interleukin-6 (IL-6), Resveratrol, Quercetin,Metformin, Berberine, Curcumine, Epigallocatechin-3-gallate (green tea),Thiazolidinediones, and Dinitrophenol (DNP).
 25. The method of claim 1,wherein the subject is also administered vitamins, minerals, and/orsupplements.